Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Nature Catalysis volume 4, pages 284–292 (2021)Cite this article

Subjects

Abstract

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(i)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Suzuki–Miyaura cross-coupling.
Fig. 2: Examining the transmetallation step using experimental and computational techniques.
Fig. 3: Examining the 13C KIE.
Fig. 4: A condensed Gibbs energy profile showing transmetallation, oxidative addition and reductive elimination.
Fig. 5: Asymmetric allylic arylation with heterocyclic allyl chlorides.
Fig. 6: Asymmetric allylic arylation with deuterium-labelled allyl chlorides and diastereomeric allyl chlorides.
Fig. 7: Simplified models showing the origins of diastereoselectivity and enantioselectivity in this Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling.

Similar content being viewed by others

Data availability

Detailed experimental methods and analytical data for all the experiments, along with absolute energies and selected distances for the DFT-computed structures and for the computed stationary points, can be found in the Supplementary Information. Cartesian coordinates (in xyz format) for the computed stationary points can be found in the Supplementary Data.

Code availability

All Python scripts used for the data analysis have been made available at https://github.com/bobbypaton under a creative commons CC-BY license.

References

  1. Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine (Wiley-VCH, 2006).

    Google Scholar 

  2. Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).

    Article  CAS  Google Scholar 

  3. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dong, L. et al. Asymmetric nitroallylation of arylboronic acids with nitroallyl acetates catalyzed by chiral rhodium complexes and its application in a concise total synthesis of optically pure (+)-γ-lycorane. Org. Lett. 7, 4285–4288 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Yu, B., Menard, F., Isosno, N. & Lautens, S. Synthesis of homoallylic alcohols via Lewis acid assisted enantioselective desymmetrization. Synthesis 2009, 853–859 (2009).

    Article  Google Scholar 

  6. Shintani, R., Takatsu, K., Takeda, M. & Hayashi, T. Copper-catalyzed asymmetric allylic substitution of allyl phosphates with aryl- and alkenylboronates. Angew. Chem. Int. Ed. 50, 8656–8659 (2011).

    Article  CAS  Google Scholar 

  7. Zhang, P., Brozek, L. A. & Morken, J. P. Pd-catalyzed enantioselective allyl–allyl cross-coupling. J. Am. Chem. Soc. 132, 10686–10688 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chung, K., Miyake, Y. & Uemura, S. Nickel(0)-catalyzed asymmetric cross-coupling reactions of allylic compounds with Grignard reagents using optically active oxazolinylferrocenylphosphines as ligands. J. Chem. Soc. Perkin Trans. 1 2000, 2725–2729 (2000).

    Article  Google Scholar 

  9. Ohmiya, H., Makida, Y., Tanaka, T. & Sawamura, M. Palladium-catalyzed γ-selective and stereospecific allyl−aryl coupling between allylic acetates and arylboronic acids. J. Am. Chem. Soc. 130, 17276–17277 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Ohmiya, H., Yokokawa, N. & Sawamura, M. Copper-catalyzed gamma-selective and stereospecific allyl–aryl coupling between (Z)-acyclic and cyclic allylic phosphates and arylboronates. Org. Lett. 12, 2438–2440 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Sidera, M. & Fletcher, S. P. Rhodium-catalyzed asymmetric allylic arylation of racemic halides with arylboronic acids. Nat. Chem. 7, 935–939 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Asymmetric Suzuki–Miyaura coupling of heterocycles via rhodium-catalyzed allylic arylation of racemates. Nat. Commun. 8, 15762 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. González, J., van Dijk, L., Goetzke, F. W. & Fletcher, S. P. Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides. Nat. Protocols 14, 2972–2985 (2019).

    Article  PubMed  Google Scholar 

  14. Goetzke, F. W., Mortimore, M. & Fletcher, S. P. Enantio- and diastereoselective Suzuki–Miyaura coupling with racemic bicycles. Angew. Chem. Int. Ed. 58, 12128–12132 (2019).

    Article  CAS  Google Scholar 

  15. Hayashi, T., Takahashi, M., Takaya, Y. & Ogasawara, M. Catalytic cycle of rhodium-catalyzed asymmetric 1,4-addition of organoboronic acids. Arylrhodium, oxa-π-allylrhodium, and hydroxorhodium intermediates. J. Am. Chem. Soc. 124, 5052–5058 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Kina, A., Iwamura, H. & Hayashi, T. A kinetic study on Rh/binap-catalyzed 1,4-addition of phenylboronic acid to enones: negative nonlinear effect caused by predominant homochiral dimer contribution. J. Am. Chem. Soc. 128, 3904–3905 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. Comprehensive Asymmetric Catalysis II (Springer, 1999).

  18. Turnbull, B. W. H. & Evans, P. A. Asymmetric rhodium-catalyzed allylic substitution reactions: discovery, development and applications to target-directed synthesis. J. Org. Chem. 83, 11463–11479 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. You, H., Rideau, E., Sidera, M. & Fletcher, S. P. Non-stabilized nucleophiles in Cu-catalyzed dynamic kinetic asymmetric allylic alkylation. Nature 517, 351–355 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Rideau, E., You, H., Sidera, M., Claridge, T. D. W. & Fletcher, S. P. Mechanistic studies on a Cu-catalyzed asymmetric allylic alkylation with cyclic racemic starting materials. J. Am. Chem. Soc. 139, 5614–5624 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Lu, Z., Wilsily, A. & Fu, G. C. Stereoconvergent amine-directed alkyl–alkyl Suzuki reactions of unactivated secondary alkyl chlorides. J. Am. Chem. Soc. 133, 8154–8157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Langlois, J., Emery, D., Mareda, J. & Alexakis, A. Mechanistic identification and improvement of a direct enantioconvergent transformation in copper-catalyzed asymmetric allylic alkylation. Chem. Sci. 3, 1062–1069 (2012).

    Article  CAS  Google Scholar 

  24. Girard, C. & Kagan, H. B. Nonlinear effects in asymmetric synthesis and stereoselective reactions: ten years of investigation. Angew. Chem. Int. Ed. 37, 2922–2959 (1998).

    Article  Google Scholar 

  25. Tsui, G. C., Menard, F. & Lautens, M. Regioselective rhodium(i)-catalyzed hydroarylation of protected allylic amines with arylboronic acids. Org. Lett. 12, 2456–2459 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, Q., Wang, Y., Luo, S. & Wang, J. Kinetic resolution and dynamic kinetic resolution of chromene by rhodium-catalyzed asymmetric hydroarylation. Angew. Chem. Int. Ed. 58, 5343–5347 (2019).

    Article  CAS  Google Scholar 

  27. Yang, X. et al. Catalytic hydrothiolation: counterion-controlled regioselectivity. J. Am. Chem. Soc. 141, 3006–3013 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mc Daniel, D. H. & Brown, H. C. An extended table of Hammett substituent constants based on the ionization of substituted benzoic acids. J. Org. Chem. 23, 420–427 (1958).

    Article  Google Scholar 

  29. Corrie, T. J. A., Ball, L. T., Russell, C. A. & Lloyd‐Jones, G. C. Au-catalyzed biaryl coupling to generate 5- to 9-membered rings: turnover-limiting reductive elimination versus π-complexation. J. Am. Chem. Soc. 139, 245–254 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Lennox, A. J. J. & Lloyd‐Jones, G. C. Transmetalation in the Suzuki–Miyaura coupling: the fork in the trail. Angew. Chem. Int. Ed. 52, 7362–7370 (2013).

    Article  CAS  Google Scholar 

  31. Thomas, A. A. & Denmark, S. E. Pre-transmetalation intermediates in the Suzuki–Miyaura reaction revealed: the missing link. Science 352, 329–332 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Yaman, T. & Harvey, J. N. Suzuki–Miyaura coupling revisited: an integrated computational study. Faraday Discuss. 220, 425–442 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Singleton, D. A. & Thomas, A. A. High-precision simultaneous determination of multiple small kinetic isotope effects at natural abundance. J. Am. Chem. Soc. 117, 9357–9358 (1995).

    Article  CAS  Google Scholar 

  34. Frantz, D. E., Singleton, D. A. & Snyder, J. P. 13C kinetic isotope effects for the addition of lithium dibutylcuprate to cyclohexenone. Reductive elimination is rate-determining. J. Am. Chem. Soc. 119, 3383–3384 (1997).

    Article  CAS  Google Scholar 

  35. Li, J. et al. Catalytic asymmetric cascade vinylogous Mukaiyama 1,6-Michael/Michael addition of 2-silyloxyfurans with azoalkenes: direct approach to fused butyrolactones. J. Am. Chem. Soc. 137, 10124–10127 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Colletto, C., Islam, S., Juliá-Hernández, F. & Larrosa, I. Room-temperature direct β-arylation of thiophenes and benzo[b]thiophenes and kinetic evidence for a Heck-type pathway. J. Am. Chem. Soc. 138, 1677–1683 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith, J. R. et al. Enantioselective rhodium(iii)-catalyzed Markovnikov hydroboration of unactivated terminal alkenes. J. Am. Chem. Soc. 139, 9148–9151 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rathbun, C. M. & Johnson, J. B. Rhodium-catalyzed acylation with quinolinyl ketones: carbon−carbon single bond activation as the turnover-limiting step of catalysis. J. Am. Chem. Soc. 133, 2031–2033 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Moore, J. L., Silvestri, A. P., de Alaniz, J. R., DiRocco, D. A. & Rovis, T. Mechanistic investigation of the enantioselective intramolecular Stetter reaction: proton transfer is the first irreversible step. Org. Lett. 13, 1742–1745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee, D. H., Kwon, K. H. & Yi, C. S. Selective catalytic C–H alkylation of alkenes with alcohols. Science 333, 1613–1616 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Meyer, M. P. New Applications of Isotope Effects in the Determination of Organic Reaction Mechanisms (Elsevier, 2012).

  42. Vo, L. K. & Singleton, D. A. Isotope effects and the nature of stereo- and regioselectivity in hydroaminations of vinylarenes catalyzed by palladium(ii)−diphosphine complexes. Org. Lett. 6, 2469–2472 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Roytman, V. A., Karugu, R. W., Hong, Y., Hirschi, J. S. & Vetticatt, M. J. 13C kinetic isotope effects as a quantitative probe to distinguish between enol and enamine mechanisms in aminocatalysis. Chem. Eur. J. 24, 8098–8102 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Wolfsberg, M., Van Hook, W. A., Paneth, P. & Rebelo, L. P. N. Isotope Effects in the Chemical, Geological, and Bio Sciences (Springer, 2010).

  45. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    Article  CAS  Google Scholar 

  46. Deb, A., Hazra, A., Peng, Q., Paton, R. S. & Maiti, D. Detailed mechanistic studies on palladium-catalyzed selective C−H olefination with aliphatic alkenes—a significant influence of proton shuttling. J. Am. Chem. Soc. 139, 763–775 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Mekareeya, A. et al. Mechanistic insight into palladium-catalyzed cycloisomerization: a combined experimental and theoretical study. J. Am. Chem. Soc. 139, 10104–10114 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Frisch, M. J. et al. Gaussian 09, Revision D.01 (Gaussian, 2009).

    Google Scholar 

  49. Straker, R., Peng, Q., Mekareeya, A., Paton, R. S. & Anderson, E. A. Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerizations. Nat. Commun. 7, 10109 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peng, Q., Duarte, F. & Paton, R. S. Computing organic stereoselectivity—from concepts to quantitative calculations and predictions. Chem. Soc. Rev. 45, 6093–6107 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Karabiyikoglu, S., Brethomé, A., Palacin, T., Paton, R. S. & Fletcher, S. P. Enantiomerically enriched tetrahydropyridine allyl chlorides. Chem. Sci. 11, 4125–4130 (2020).

    Article  CAS  Google Scholar 

  52. Mackenzie, P. B., Whelan, J. & Bosnich, B. Asymmetric synthesis. Mechanism of asymmetric catalytic allylation. J. Am. Chem. Soc. 107, 2046–2054 (1985).

    Article  CAS  Google Scholar 

  53. Lloyd‐Jones, G. C. & Stephen, S. C. Memory effects in Pd‐catalysed allylic alkylation: stereochemical labelling through isotopic desymmetrization. Chem. Eur. J. 4, 2539–2549 (1998).

    Article  Google Scholar 

  54. Lloyd‐Jones, G. C. et al. Conclusive evidence for a retention−retention pathway for the molybdenum-catalyzed asymmetric alkylation. J. Am. Chem. Soc. 126, 702–703 (2004).

    Article  PubMed  Google Scholar 

  55. Madrahimov, S. T. & Hartwig, J. F. Origins of enantioselectivity during allylic substitution reactions catalyzed by metallacyclic iridium complexes. J. Am. Chem. Soc. 134, 8136–8147 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Granberg, K. L. & Bäckvall, J. E. Isomerization of (π-allyl)palladium complexes via nucleophilic displacement by palladium(0). A common mechanism in palladium(0)-catalyzed allylic substitution. J. Am. Chem. Soc. 114, 6858–6863 (1992).

    Article  CAS  Google Scholar 

  57. Falivene, L. et al. Towards the online computer-aided design of catalytic pockets. Nat. Chem. 11, 872–879 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The EPSRC supports this work though standard grant EP/N022246/1. L.v.D. and R.A. thank the EPSRC Centre for Doctoral Training (CDT) in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. R.A. also acknowledges the Development and Promotion of Science and Technology Talents Project and the Royal Thai Government. This material is based on work supported by the National Science Foundation under Grant no. 1955876. We used the Dirac cluster at Oxford supported by the EPSRC CDT for Theory and Modelling in Chemical Sciences (EP/L015722/1), the RMACC Summit supercomputer, which is supported by the National Science Foundation (ACI-1532235 and ACI-1532236), the University of Colorado Boulder and Colorado State University, and the Extreme Science and Engineering Discovery Environment (XSEDE) through allocation TG-CHE180056 and computing resources provided by the National e-Science Infrastructure Consortium, Thailand. O.S. thanks the Scientific and Technological Research Council of Turkey for the 2214-A Scholarship Programme. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. [838616].

Author information

Author notes

  1. These authors contributed equally: Lucy van Dijk, Ruchuta Ardkhean, Mireia Sidera.

Authors and Affiliations

  1. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

    Lucy van Dijk, Ruchuta Ardkhean, Mireia Sidera, Sedef Karabiyikoglu, Özlem Sari, Timothy D. W. Claridge, Robert S. Paton & Stephen P. Fletcher

  2. Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand

    Ruchuta Ardkhean

  3. Vertex Pharmaceuticals (Europe) Ltd, Milton Park, UK

    Mireia Sidera

  4. Department of Chemistry, Middle East Technical University, Ankara, Turkey

    Özlem Sari

  5. Department of Chemistry, Kirsehir Ahi Evran University, Kirsehir, Turkey

    Özlem Sari

  6. EaStChem, University of Edinburgh, Edinburgh, UK

    Guy C. Lloyd-Jones

  7. Department of Chemistry, Colorado State University, Fort Collins, CO, USA

    Robert S. Paton

Authors
  1. Lucy van Dijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruchuta Ardkhean
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mireia Sidera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sedef Karabiyikoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Özlem Sari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Timothy D. W. Claridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guy C. Lloyd-Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert S. Paton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen P. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.P.F. conceived and directed the project. S.P.F., L.v.D. and M.S. designed the experiments. L.v.D., M.S. and S.K. performed the experiments. L.v.D., R.A., M.S., R.S.P., G.C.L.-J. and S.P.F. analysed the experimental results. R.S.P, L.v.D., R.A. and O.S. designed, conducted and analysed the computational work. T.D.W.C. designed and performed the 13C NMR experiments. G.C.L.-J. derived the pseudo steady-state rate equation. L.v.D. and S.P.F. wrote the manuscript with contributions from R.S.P., G.C.L.-J., T.D.W.C., M.S. and R.A.

Corresponding authors

Correspondence to Timothy D. W. Claridge, Guy C. Lloyd-Jones, Robert S. Paton or Stephen P. Fletcher.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Catalysis thanks Per-Ola Norrby and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–8, Tables 1–26, Methods, Discussion and References.

Supplementary Data

Co-ordinates of computed structures in xyz format.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Dijk, L., Ardkhean, R., Sidera, M. et al. Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides. Nat Catal 4, 284–292 (2021). https://doi.org/10.1038/s41929-021-00589-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-021-00589-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing